From the Department of Optometry and Vision Sciences (A.C.B.-J., S.A.G., L.N.A.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia; Department of Surgery (Ophthalmology) (A.C.B.-J., S.A.G., K.L.G., T.L.E.., L.N.A.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia; Centre for Eye Research Australia (A.C.B.-J., S.A.G., K.L.G., T.L.E., L.N.A.), Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
From the Department of Optometry and Vision Sciences (A.C.B.-J., S.A.G., L.N.A.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia; Department of Surgery (Ophthalmology) (A.C.B.-J., S.A.G., K.L.G., T.L.E.., L.N.A.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia; Centre for Eye Research Australia (A.C.B.-J., S.A.G., K.L.G., T.L.E., L.N.A.), Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
Am J Ophthalmol. 2023 May;249:57-73. doi: 10.1016/j.ajo.2022.12.027. Epub 2022 Dec 30.
Accurate genotyping of individuals with inherited retinal diseases (IRD) is essential for patient management and identifying suitable candidates for gene therapies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs.
Systematic review and meta-analysis.
This systematic review was prospectively registered (CRD42021293619). Ovid MEDLINE and Ovid Embase were searched on 6 June 2022. Clinical studies evaluating the diagnostic yield of NGS in individuals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random...effects inverse variance model. Sources of heterogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis.
This study included 105 publications from 28 countries. Most studies (90 studies) used targeted gene panels. The diagnostic yield of NGS was 61.3% (95% confidence interval: 57.8-64.7%; 51 studies) in mixed IRD phenotypes, 58.2% (51.6-64.6%; 41 studies) in rod-cone dystrophies, 57.7% (46.8-68.3%; eight studies) in macular and cone/cone-rod dystrophies, and 47.6% (95% CI: 41.0-54.3%; four studies) in familial exudative vitreoretinopathy. For mixed IRD phenotypes, a higher diagnostic yield was achieved pooling studies published between 2018-2022 (64.2% [59.5-68.7%]), studies using exome sequencing (73.5% [58.9-86.1%]), and studies using the American College of Medical Genetics variant interpretation standards (65.6% [60.8-70.4%]).
The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evidence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity between studies. Adoption of standardized reporting guidelines could improve confidence in future meta-analyses.
准确进行遗传性视网膜疾病（IRD）个体的基因分型对于患者管理和鉴定基因治疗的合适候选者至关重要。本研究评估了下一代测序（NGS）在 IRD 中的诊断效能。
系统评价和荟萃分析。
本系统评价前瞻性注册（CRD42021293619）。于 2022 年 6 月 6 日检索 Ovid MEDLINE 和 Ovid Embase。纳入评估 NGS 在 IRD 个体中诊断效能的临床研究。进行了偏倚风险评估。使用随机效应逆方差模型进行汇总分析。使用分层分析、荟萃回归和敏感性分析探索异质性来源。
本研究纳入了来自 28 个国家的 105 篇文献。大多数研究（90 项研究）使用了靶向基因面板。在混合 IRD 表型中，NGS 的诊断效能为 61.3%（95%置信区间：57.8-64.7%；51 项研究），在杆锥营养不良中为 58.2%（51.6-64.6%；41 项研究），在黄斑和锥/圆锥-杆营养不良中为 57.7%（46.8-68.3%；8 项研究），在家族性渗出性玻璃体视网膜病变中为 47.6%（95%置信区间：41.0-54.3%；4 项研究）。对于混合 IRD 表型，在汇总 2018-2022 年发表的研究（64.2%[59.5-68.7%]）、使用外显子组测序的研究（73.5%[58.9-86.1%]）和使用美国医学遗传学学院变异解读标准的研究（65.6%[60.8-70.4%]）时，诊断效能更高。
目前 NGS 在 IRD 中的诊断效能在 52%-74%之间。证据的确定性被判断为低或极低。目前证据的一个关键局限性是研究之间存在显著的异质性。采用标准化报告指南可以提高对未来荟萃分析的信心。
